The overarching goal of this proposal is to elucidate the role of altered activity of translation initiation complex eIF4F, and the efficacy of inhibition of individual members of the eIF4F complex in the selective translation, survival, proliferation, and radio- resistance by the cancer stem cell (CSC, or tumor-initiating cell) in one of the most deadly presentations of advanced breast cancer, high grade, advanced stage inflammatory breast cancer (IBC). We plan to achieve this goal by a combination of silencing and targeted treatment of individual components of the eIF4F complex, as well as of their regulators, followed by irradiation and examination in the changes in the population of CSCs as well as the associated changes in translation signatures as determined by microarray analysis of the polysome-associated, actively translating mRNAs in the treated and untreated CSCs. The availability of several drugs in different stages of development targeting eIF4F components, coupled with their direct downregulation by shRNA silencing, will provide us with a rapid way to test the possibility to sensitize IBC CSCs to radiotherapy in anticipation for these inhibitors entering the clinic. PUBLIC HEALTH RELEVANCE: The proposed study is aimed at investigating the effect of targeting the protein synthesis machinery, by both downregulation of specific factors or the use of specific drugs, in order to increase the efficacy of radiotherapy in the eliminating the cancer stem cell population (CSC, or tumor-initiating cell), implicated in both recurrence and metastasis, in one of the most deadly presentations of advanced breast cancer, high grade, advanced stage inflammatory breast cancer (IBC).